Cardiac-targeted transgenic mutant mitochondrial enzymes: MtDNA defects, antiretroviral toxicity and cardiomyopathy
Cardiac-targeted transgenic mutant mitochondrial enzymes: MtDNA defects, antiretroviral toxicity and cardiomyopathy
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DOI：
10.1007/s12012-008-9015-1
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发表时间：
2008-06-01
影响因子：
3.2
通讯作者：
Lewis, William
中科院分区：
文献类型：
--
作者：
Kohler, James J.;Hosseini, Seyed H.;Lewis, William
线粒体（mt）DNA生物合成对心肌收缩力至关重要。DNA聚合酶γ（Pol γ）复制mtDNA，而胸苷激酶2（TK 2）在尿道内使嘧啶单磷酸化。POLG和TK 2的点突变导致与mtDNA缺失和器官功能障碍相关的临床疾病。嘧啶类似物（NRTI）抑制Pol γ和mtDNA复制。心脏“显性阴性”鼠转基因（TG; Pol γ Y 955 C和TK 2 H121 N或I212 N）定义了每种转基因在心脏中的作用。在有或没有嘧啶类似物的“2 × 2”研究中，测定TG的mtDNA丰度、组织病理学特征、组织化学、线粒体蛋白丰度、形态学和超声心动图。Y 955 C TG中心脏线粒体DNA丰度下降（接近50%），但H121 N和I212 N TG中增加（20-70%）。琥珀酸脱氢酶（SDH）增加，在所有的突变体的心脏。Y 955 C和H121 N TG的超微结构发生了变化。组织学显示H121 N肥大，I212 N LV扩张，Y 955 C TG肥大和扩张。抗逆转录病毒药物增加了所有三种TG的LV质量（约50%），结合扩张表明心肌病。总之，这些研究证明了心功能不全的三种表现，这取决于特定突变的性质和抗逆转录病毒治疗。线粒体DNA生物发生基因突变增加了线粒体DNA复制缺陷的风险，导致左心室肥大。
Mitochondrial (mt) DNA biogenesis is critical to cardiac contractility. DNA polymerase gamma (Pol gamma) replicates mtDNA, whereas thymidine kinase 2 (TK2) monophosphorylates pyrimidines intramitochondrially. Point mutations in POLG and TK2 result in clinical diseases associated with mtDNA depletion and organ dysfunction. Pyrimidine analogs (NRTIs) inhibit Pol gamma and mtDNA replication. Cardiac "dominant negative" murine transgenes (TGs; Pol gamma Y955C, and TK2 H121N or I212N) defined the role of each in the heart. mtDNA abundance, histopathological features, histochemistry, mitochondrial protein abundance, morphometry, and echocardiography were determined for TGs in "2 x 2" studies with or without pyrimidine analogs. Cardiac mtDNA abundance decreased in Y955C TGs (similar to 50%) but increased in H121N and I212N TGs (20-70%). Succinate dehydrogenase (SDH) increased in hearts of all mutants. Ultrastructural changes occurred in Y955C and H121N TGs. Histopathology demonstrated hypertrophy in H121N, LV dilation in I212N, and both hypertrophy and dilation in Y955C TGs. Antiretrovirals increased LV mass (approximate to 50%) for all three TGs which combined with dilation indicates cardiomyopathy. Taken together, these studies demonstrate three manifestations of cardiac dysfunction that depend on the nature of the specific mutation and antiretroviral treatment. Mutations in genes for mtDNA biogenesis increase risk for defective mtDNA replication, leading to LV hypertrophy.